The central nervous system develops over a protracted period; yet, there are two times of notable vulnerability to ethanol toxicity- during fetal and adolescent development. These are also times that are of critical clinical importance because many are exposed to alcohol during fetal and adolescent life. The ongoing developmental events in the fetus and adolescent are quite different, thus the potential for ethanolinduced changes also differ. Seminal events in fetal development and during adolescence are the definition of cell fate and dendritic growth and refinement, respectively. The present study will explore the effects of ethanol on these processes by testing the hypotheses that (1) ethanol affects CNS composition by altering the fates of undetermined neuronal progenitors, (2) ethanol affects synaptic connections that are remodeled during adolescence in a time-dependent manner, and (3) plasticity in the adolescent is primed by alterations in fetal development and that such changes in the adolescent establish long-term changes in brain structure in the adult. The focus will be the cerebral cortex because it is critical for activities such as learning, memory, and executive function, acknowledged behavioral targets of ethanol. These studies will exploit transgenic mice that have a select population of neurons, pyramidal neurons in layer V, that endogenously fluoresce. Studies will determine (1) the effects of fetal ethanol exposure on neuronal fate and the contribution of the transcription factor Foxgl in that process, (2) the effects of adolescent ethanol exposure on dendritic, spine, and synaptic plasticity and the role of excitatory and inhibitory neurotransmitter systems in that plasticity, and (3) whether fetal and additional adolescent exposure combine for greater and potentially permanent changes in cortical structure. Thus, the goal of this project is to test the alcoholism generator hypothesis central to the DEARC- that fetal programming sets up the structure of the adult brain and that this process is exacerbated by adolescent exposure to ethanol.